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Clin Epigenetics. 2019 Apr 8;11(1):60. doi: 10.1186/s13148-019-0655-8.

Novel parent-of-origin-specific differentially methylated loci on chromosome 16.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
2
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
3
Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
4
Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
5
Division of Genetics and Genomic Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
6
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
7
Texas Children's Hospital, Houston, TX, USA.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. hanchard@bcm.edu.
9
USDA/ARS/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA. hanchard@bcm.edu.
10
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. pawels@bcm.edu.

Abstract

BACKGROUND:

Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants.

RESULTS:

To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with ≥ 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer.

CONCLUSIONS:

Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV.

KEYWORDS:

ACDMPV; CpG; Imprinting; Trisomy 16; Uniparental disomy 16

PMID:
30961659
DOI:
10.1186/s13148-019-0655-8
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